Bromodomain Inhibitors

Abstract

wherein R1, Y, L1, G1, X1, X2, L2, R2, R3, and R4 have any of the values defined in the specification, and pharmaceutically acceptable salts thereof, that are useful as agents in the treatment of diseases and conditions, including inflammatory diseases, cancer, and AIDS. Also provided are pharmaceutical compositions comprising compounds of formula (I).

1 . A compound of formula (I) or a pharmaceutically acceptable salt thereof, 
       
         
           
           
               
               
           
         
         wherein 
         R 1  is C 1 -C 3  alkyl; 
         Y is N or C(R Y ) wherein R Y  is hydrogen or C 1 -C 3  alkyl; 
         L is O or N(R x ) wherein R x  is hydrogen or C 1 -C 3  alkyl; 
         G 1  is a 4-11 membered monocyclic, bicyclic, or polycyclic hydrocarbon ring with zero, one, or two double bonds, wherein one or two carbon ring atoms of G 1  are optionally replaced by heteroatoms selected from the group consisting of N, O, and S; the rings within the polycyclic and bicyclic are in a bridged, fused, or spiro orientation, or combinations thereof, each G 1  is substituted with 1, 2, 3, or 4 substituents wherein one of the substituents is an R 1g  group, and the optional substituents of G 1  are independently selected from the group consisting of C 1 -C 3  alkyl, C 1 -C 3  haloalkyl, halogen, —CN, —OR 2g , —N(R 2g ) 2 , —C(O)R 2g , cyclopropyl, and cyclobutyl; wherein each R 2g  is independently hydrogen, C 1 -C 3  alkyl, or C 1 -C 3  haloalkyl; 
         R 1g  is —CN, G 1A , —OR b , —C(O)R b , —C(O)OR c , —C(O)N(R b ) 2 , —S(O) 2 R b , —N(R a )S(O) 2 R b , —N(R a )C(O)R b , —N(R a )C(O)C(O)R b , —N(R d )N(R c )C(O)R b , —N(R a )C(O)OR b , —N(R d )N(R c )C(O)OR b , —N(R a )C(O)N(R b ) 2 , —N(R a )(C 1 -C 3  alkylenyl)-C(O)R b , —N(R a )(C 1 -C 3  alkylenyl)-S(O) 2 R b , or C 1 -C 6  alkyl substituted with an substituent selected from the group consisting of —OR b , —C(O)R b , —C(O)OR c , —C(O)N(R b ) 2 , —S(O) 2 R b , —N(R a )S(O) 2 R b , —N(R a )C(O)R b , —N(R a )C(O)OR b , and —N(R a )C(O)N(R b ) 2 , 
         R a , at each occurrence, is independently hydrogen, C 1 -C 6  alkyl, C 1 -C 6  haloalkyl, C 2 -C 6  alkenyl, —N(R j ) 2 , —(C 2 -C 6  alkylenyl)-OR j , or —(C 1 -C 6  alkylenyl)-C(O)OR j ; 
         R b , at each occurrence, is independently hydrogen, C 1 -C 6  alkyl, C 2 -C 6  alkenyl, C 1 -C 6  haloalkyl, G 1B , —(C 1 -C 6  alkylenyl)-OR j , —(C 1 -C 6  alkylenyl)-N(R j ) 2 , or —(C 1 -C 6  alkylenyl)-C(O)OR j ; 
         R c , at each occurrence, is independently hydrogen, C 1 -C 6  alkyl, C 2 -C 6  alkenyl, or C 1 -C 6  haloalkyl; 
         R d , at each occurrence, is independently hydrogen, C 1 -C 6  alkyl, C 2 -C 6  alkenyl, C 1 -C 6  haloalkyl, or —C(O)R b ; 
         G 1A  is phenyl, C 3 -C 11  cycloalkyl, 4-11 membered heterocycle, or 5-11 membered heteroaryl; wherein each G 1A  is optionally substituted with 1, 2, 3, 4, or 5 independently selected R s  groups; 
         G 1B  is phenyl, C 3 -C 11  cycloalkyl, 4-11 membered heterocycle, or 5-11 membered heteroaryl; 
         wherein each G 1B  is optionally substituted with 1, 2, 3, or 4 independently R t  groups; 
         L 2  is O or N(R e ) wherein R e  is hydrogen or C 1 -C 3  alkyl; 
         R 2  is phenyl or monocyclic heteroaryl; each R 2  is substituted with 2, 3, or 4 substituents wherein two of the substituents are independently selected from the group consisting of halogen, C 1 -C 6  alkyl, and C 1 -C 6  haloalkyl, and the optional substituents are independently selected from the group consisting of halogen, —CN, C 1 -C 6  alkyl, C 1 -C 6  haloalkyl, —S(C 1 -C 6  alkyl), —S(O) 2 (C 1 -C 6  alkyl), and —(C 2 -C 6  alkylenyl)-OH; 
         R 3  is hydrogen, halogen, —CN, C 1 -C 6  haloalkyl, or C 1 -C 6  alkyl; 
         R 4  is 
       
       
         
           
           
               
               
           
         
         wherein 
         R 4a  is C 1 -C 6  alkyl or C 1 -C 6  haloalkyl, wherein the C 1 -C 6  alkyl and the C 1 -C 6  haloalkyl are each optionally substituted with one substituent selected from the group consisting of —OH and —CN; 
         R 4b  is C 1 -C 6  alkyl or C 1 -C 6  haloalkyl; 
         R 4c  and R 4d  are each independently hydrogen, C 1 -C 6  alkyl, or C 1 -C 6  haloalkyl; 
         R 4e  is hydrogen, C 1 -C 3  alkyl, C 2 -C 4  alkenyl, C 1 -C 3  haloalkyl, or —(C 1 -C 3  alkylenyl)-G 1C ; wherein G 1C  is phenyl, monocyclic heteroaryl, monocyclic C 3 -C 6  cycloalkyl, or 4-6 membered monocyclic heterocycle; wherein each G 1C  is optionally substituted with 1, 2, 3, or 4 independently selected R u  groups; 
         R 4f  is C 1 -C 3  alkyl, C 2 -C 4  alkenyl, C 1 -C 3  haloalkyl, —C(O)R 4cc , or —C(O)N(R 4cd )(R 4ce ); wherein R 4cc  is C 1 -C 3  alkyl, C 2 -C 4  alkenyl, or C 1 -C 3  haloalkyl; and R 4cd  and R 4ce  are each independently hydrogen, C 1 -C 3  alkyl, C 2 -C 4  alkenyl, or C 1 -C 3  haloalkyl; 
         X 1  and X 2  are C(R 5 ) or 
         one of X 1  and X 2  is N and the other is C(R 5 ); 
         R 5 , at each occurrence, is independently hydrogen or halogen; 
         R s , R t , and R u , at each occurrence, are each independently C 1 -C 6  alkyl, C 2 -C 6  alkenyl, C 2 -C 6  alkynyl, halogen, C 1 -C 6  haloalkyl, —CN, oxo, NO 2 , —OR j , —OC(O)R k , —OC(O)N(R j ) 2 , —SR j , —S(O) 2 R j , —S(O) 2 N(R j ) 2 , —C(O)R j , —C(O)OR j , —C(O)N(R j ) 2 , —C(O)N(R j )S(O) 2 R k , —N(R j ) 2 , —N(R j )C(O)R k , —N(R j )S(O) 2 R k , —N(R j )C(O)O(R k ), —N(R j )C(O)N(R j ) 2 , —(C 1 -C 6  alkylenyl)-OR j , —(C 1 -C 6  alkylenyl)-OC(O)R k , —(C 1 -C 6  alkylenyl)-OC(O)N(R j ) 2 , —(C 1 -C 6  alkylenyl)-SR j , —(C 1 -C 6  alkylenyl)-S(O) 2 R j , —(C 1 -C 6  alkylenyl)-S(O) 2 N(R j ) 2 , —(C 1 -C 6  alkylenyl)-C(O)R j , —(C 1 -C 6  alkylenyl)-C(O)OR j , —(C 1 -C 6  alkylenyl)-C(O)N(R j ) 2 , —(C 1 -C 6  alkylenyl)-C(O)N(R j )S(O) 2 R k , —(C 1 -C 6  alkylenyl)-N(R j ) 2 , —(C 1 -C 6  alkylenyl)-N(R j )C(O)R k , —(C 1 -C 6  alkylenyl)-N(R j )S(O) 2 R k , —(C 1 -C 6  alkylenyl)-N(R j )C(O)O(R k ), —(C 1 -C 6  alkylenyl)-N(R j )C(O)N(R j ) 2 , or —(C 1 -C 6  alkylenyl)-CN; 
         R j , at each occurrence, is independently hydrogen, C 1 -C 6  alkyl, or C 1 -C 6  haloalkyl; and 
         R k , at each occurrence, is independently C 1 -C 6  alkyl or C 1 -C 6  haloalkyl. 
       
     
     
         2 . The compound of  claim 1  or a pharmaceutically acceptable salt thereof, wherein
 G 1  is monocyclic C 3 -C 6  cycloalkyl, spiro[3.3]heptanyl, or a 4-6 membered monocyclic heterocycle; and each G 1  is substituted with 1, 2, 3, or 4 substituents wherein one of the substituents is an R 1g  group, and the optional substituents of G 1  are independently selected from the group consisting of C 1 -C 3  alkyl, C 1 -C 3  haloalkyl, halogen, —CN, —OR 2g , —N(R 2g ) 2 , —C(O)R 2g , cyclopropyl, and cyclobutyl; wherein each R 2g  is independently hydrogen, C 1 -C 3  alkyl, or C 1 -C 3  haloalkyl. 
 
     
     
         3 . The compound of  claim 1  or a pharmaceutically acceptable salt thereof, wherein
 G 1  is cyclobutyl, cyclopentyl, cyclohexyl, spiro[3.3]heptanyl, pyrrolidinyl, or piperidinyl; and each G 1  is substituted with 1, 2, 3, or 4 substituents wherein one of the substituents is an R 1g  group, and the optional substituents are independently selected from the group consisting of C 1 -C 3  alkyl, C 1 -C 3  haloalkyl, and halogen; and 
 R 1g  is —CN, G 1A , —OR b , —C(O)R b , —C(O)OR c , —C(O)N(R b ) 2 , —S(O) 2 R b , —N(R a )S(O) 2 R b , —N(R a )C(O)R b , —N(R a )C(O)C(O)R b , —N(R a )C(O)OR b , or C 1 -C 6  alkyl substituted with an substituent selected from the group consisting of —OR b , —N(R a )C(O)R b , and —N(R a )C(O)OR b . 
 
     
     
         4 . The compound of  claim 3  or a pharmaceutically acceptable salt thereof, wherein
 R 1g  is G 1A , —N(R a )C(O)R b , or —N(R a )C(O)OR b . 
 
     
     
         5 . The compound of  claim 1  or a pharmaceutically acceptable salt thereof, wherein
 Y is C(R Y ); 
 X 1  is N or C(R 5 ); and 
 X 2  is C(R 5 ). 
 
     
     
         6 . The compound of  claim 1  or a pharmaceutically acceptable salt thereof, wherein
 L 2  is O and 
 R 2  is phenyl which is substituted with 2, 3, or 4 substituents wherein two of the substituents are independently selected from the group consisting of halogen, C 1 -C 6  alkyl, and C 1 -C 6  haloalkyl, and the optional substituents are independently selected from the group consisting of halogen, —CN, C 1 -C 6  alkyl, C 1 -C 6  haloalkyl, —S(C 1 -C 6  alkyl), —S(O) 2 (C 1 -C 6  alkyl), and —(C 2 -C 6  alkylenyl)-OH. 
 
     
     
         7 . The compound of  claim 1  of formula (I) or a pharmaceutically acceptable salt thereof, wherein R 4  is 
       
         
           
           
               
               
           
         
       
     
     
         8 . The compound of  claim 1  of formula (I) or a pharmaceutically acceptable salt thereof, wherein R 4  is 
       
         
           
           
               
               
           
         
       
     
     
         9 . The compound of  claim 1  of formula (I-a) or a pharmaceutically acceptable salt thereof, 
       
         
           
           
               
               
           
         
         wherein 
         X 3  is N, C(H), or C(R 6 ); 
         each R 6  is independently C 1 -C 3  alkyl, C 1 -C 3  haloalkyl, or halogen; 
         m is 0, 1, or 2; and 
         R 1 , Y, L 1 , R 1g , X 1 , X 2 , L 2 , R 2 , R 3 , and R 4  are as set forth in  claim 1 . 
       
     
     
         10 . The compound of  claim 9  or a pharmaceutically acceptable salt thereof, wherein
 R 1g  is —CN, G 1A , —C(O)R b , —C(O)OR c , —C(O)N(R b ) 2 , —S(O) 2 R b , —N(R a )S(O) 2 R b , —N(R a )C(O)R b , —N(R a )C(O)OR b , or C 1 -C 6  alkyl substituted with an —OR b . 
 
     
     
         11 . The compound of  claim 9  or a pharmaceutically acceptable salt thereof, wherein
 R 1g  is G 1A , —N(R a )C(O)R b , or —N(R a )C(O)OR b . 
 
     
     
         12 . The compound of  claim 9  or a pharmaceutically acceptable salt thereof, wherein
 R 4  is 
 
       
         
           
           
               
               
           
         
         R 4a  is C 1 -C 6  alkyl or C 1 -C 6  haloalkyl, wherein the C 1 -C 6  alkyl and the C 1 -C 6  haloalkyl are each optionally substituted with one —OH; and 
         R 4b  is C 1 -C 6  alkyl or C 1 -C 6  haloalkyl. 
       
     
     
         13 . The compound of  claim 9  or a pharmaceutically acceptable salt thereof, wherein
 R 4  is 
 
       
         
           
           
               
               
           
         
         R 4e  is hydrogen, C 1 -C 3  alkyl, or —(C 1 -C 3  alkylenyl)-G 1C  wherein G 1C  is optionally substituted phenyl; and 
         R 4f  is —C(O)R 4cc  or —C(O)N(R 4cd )(R 4ce ). 
       
     
     
         14 . The compound of  claim 9  or a pharmaceutically acceptable salt thereof, wherein
 L 2  is O; 
 X 1  is N or C(R 5 ); 
 X 2  is C(R 5 ); and 
 L 1  is O or N(R x ) wherein R x  is hydrogen. 
 
     
     
         15 . The compound of  claim 14  or a pharmaceutically acceptable salt thereof, wherein
 R 1g  is G 1A , —N(R a )C(O)R b , or —N(R a )C(O)OR b . 
 
     
     
         16 . The compound of  claim 15  or a pharmaceutically acceptable salt thereof, wherein
 R 2  is phenyl which is substituted with 2, 3, or 4 substituents wherein two of the substituents are independently selected from the group consisting of halogen, C 1 -C 6  alkyl, and C 1 -C 6  haloalkyl, and the optional substituents are independently selected from the group consisting of halogen and —(C 2 -C 6  alkylenyl)-OH. 
 
     
     
         17 . The compound of  claim 16  or a pharmaceutically acceptable salt thereof, wherein
 R 4  is 
 
       
         
           
           
               
               
           
         
       
       and
 R 4a  and R 4b  are each independently C 1 -C 6  alkyl or C 1 -C 6  haloalkyl. 
 
     
     
         18 . The compound of  claim 16  or a pharmaceutically acceptable salt thereof, wherein
 R 4  is 
 
       
         
           
           
               
               
           
         
         R 4e  is hydrogen, C 1 -C 3  alkyl, or —(C 1 -C 3  alkylenyl)-G 1C  wherein G 1C  is optionally substituted phenyl; and 
         R 4f  is —C(O)R 4cc  wherein R 4cc  is C 1 -C 3  alkyl; or R 4f  is —C(O)N(R 4cd )(R 4ce ) wherein R 4cd  and R 4ce  are hydrogen. 
       
     
     
         19 . The compound of  claim 1  of formula (I-b) or a pharmaceutically acceptable salt thereof, 
       
         
           
           
               
               
           
         
         wherein 
         each R 6  is independently C 1 -C 3  alkyl, C 1 -C 3  haloalkyl, or halogen; 
         m is 0, 1, or 2; and 
         R 1 , Y, L 1 , R 1g , X 1 , X 2 , L 2 , R 2 , R 3 , and R 4  are as set forth in  claim 1 . 
       
     
     
         20 . The compound of  claim 19  or a pharmaceutically acceptable salt thereof, wherein the substituents are selected from the group consisting of:
 (i) R1 g is G1A, N(Ra)C(O)Rb, or N(Ra)C(O)Orb; 
 (ii) R 4  is 
 
       
         
           
           
               
               
           
         
         (iii) L 2  is O;
 X 1  is N or C(R 5 ); 
 X 2  is C(R 5 ), and 
 L 1  is O or N(R x ) wherein R Y  is hydrogen, and 
 
         (iv) R 1g  is G 1A , —N(R a )C(O)R b , or —N(R a )C(O)OR b . 
       
     
     
         21 - 23 . (canceled) 
     
     
         24 . The compound of  claim 20  or a pharmaceutically acceptable salt thereof, wherein the substituents are selected from the group consisting of:
 (i) R 4  is 
 
       
         
           
           
               
               
           
         
       
       and
 (ii) R 4  is 
 
       
         
           
           
               
               
           
         
         R 4c  and R 4d  are each independently hydrogen or C 1 -C 6  alkyl; 
         R 4e  is hydrogen, C 1 -C 3  alkyl, or —(C 1 -C 3  alkylenyl)-G 1C  wherein G 1C  is optionally substituted phenyl; and 
         R 4f  is —C(O)R 4cc  wherein R 4cc  is C 1 -C 3  alkyl; or R 4f  is —C(O)N(R 4cd )(R 4cc ) wherein R 4cd  and R 4ce  are hydrogen. 
       
     
     
         25 . (canceled) 
     
     
         26 . The compound of  claim 24 , or a pharmaceutically acceptable salt thereof, wherein the substituents are selected from the group consisting of:
 (i) Y is C(R Y ); and
 X 1  and X 2  are C(R 5 ); and 
   (ii) Y is C(R Y );
 X 1  is N; and 
 X 2  is C(R 5 ). 
   
     
     
         27 - 28 . (canceled) 
     
     
         29 . A pharmaceutical composition comprising a therapeutically effective amount of a compound of formula (I) according to  claim 1 , or a pharmaceutically acceptable salt thereof, in combination with a pharmaceutically acceptable carrier. 
     
     
         30 . A method for treating cancer in a subject comprising administering a therapeutically effective amount of a compound of formula (I) according to  claim 1  or a pharmaceutically acceptable salt thereof, to a subject in need thereof. 
     
     
         31 . The method of  claim 30  wherein the cancer is selected from the group consisting of: acoustic neuroma, acute leukemia, acute lymphocytic leukemia, acute myelocytic leukemia (monocytic, myeloblastic, adenocarcinoma, angiosarcoma, astrocytoma, myelomonocytic and promyelocytic), acute t-cell leukemia, basal cell carcinoma, bile duct carcinoma, bladder cancer, brain cancer, breast cancer, bronchogenic carcinoma, cervical cancer, chondrosarcoma, chordoma, choriocarcinoma, chronic leukemia, chronic lymphocytic leukemia, chronic myelocytic (granulocytic) leukemia, chronic myelogenous leukemia, colon cancer, colorectal cancer, craniopharyngioma, cystadenocarcinoma, diffuse large B-cell lymphoma, dysproliferative changes (dysplasias and metaplasias), embryonal carcinoma, endometrial cancer, endotheliosarcoma, ependymoma, epithelial carcinoma, erythroleukemia, esophageal cancer, estrogen-receptor positive breast cancer, essential thrombocythemia, Ewing's tumor, fibrosarcoma, follicular lymphoma, germ cell testicular cancer, glioma, glioblastoma, gliosarcoma, heavy chain disease, hemangioblastoma, hepatoma, hepatocellular cancer, hormone insensitive prostate cancer, leiomyosarcoma, leukemia, liposarcoma, lung cancer, lymphagioendotheliosarcoma, lymphangiosarcoma, lymphoblastic leukemia, lymphoma (Hodgkin's and non-Hodgkin's), malignancies and hyperproliferative disorders of the bladder, breast, colon, lung, ovaries, pancreas, prostate, skin, and uterus, lymphoid malignancies of T-cell or B-cell origin, leukemia, lymphoma, medullary carcinoma, medulloblastoma, melanoma, meningioma, mesothelioma, multiple myeloma, myelogenous leukemia, myeloma, myxosarcoma, neuroblastoma, NUT midline carcinoma (NMC), non-small cell lung cancer, oligodendroglioma, oral cancer, osteogenic sarcoma, ovarian cancer, pancreatic cancer, papillary adenocarcinomas, papillary carcinoma, pinealoma, polycythemia vera, prostate cancer, rectal cancer, renal cell carcinoma, retinoblastoma, rhabdomyosarcoma, sarcoma, sebaceous gland carcinoma, seminoma, skin cancer, small cell lung carcinoma, solid tumors (carcinomas and sarcomas), small cell lung cancer, stomach cancer, squamous cell carcinoma, synovioma, sweat gland carcinoma, thyroid cancer, Waldenstrom's macroglobulinemia, testicular tumors, uterine cancer, and Wilms' tumor, Addison's disease acute gout ankylosing spondylitis asthma, atherosclerosis, Behcet's disease, bullous skin diseases, chronic obstructive pulmonary disease (COPD), Crohn's disease, dermatitis, eczema, giant cell arteritis, glomerulonephritis, hepatitis, hypophysitis, inflammatory bowel disease, Kawasaki disease, lupus nephritis, multiple sclerosis, myocarditis, myositis nephritis, organ transplant rejection, osteoarthritis, pancreatitis, pericarditis, polyarteritis nodosa, pneumonitis, primary biliary cirrhosis, psoriasis, psoriatic arthritis, rheumatoid arthritis, scleritis, sclerosing cholangitis, sepsis, systemic lupus erythematosus, Takayasu's Arteritis, toxic shock, thyroiditis, type I diabetes, ulcerative colitis, uveitis, vitiligo, vasculitis, Wegener's granulomatosis; immunodeficiency syndrome (AIDS); obesity, dyslipidemia, hypercholesterolemia, Alzheimer's disease, metabolic syndrome, hepatic steatosis, dyslipdemia, insulin resistance, diabetic retinopathy, diabetic neuropathy, male contraception, ischemia-reperfusion induced kidney disease, cardiac and major surgery induced kidney disease, percutaneous coronary intervention induced kidney disease, radio-contrast agent induced kidney disease, sepsis induced kidney disease, pneumonia induced kidney disease, drug toxicity induced kidney disease, diabetic nephropathy, hypertensive nephropathy, HIV-associated nephropathy, glomerulonephritis, lupus nephritis, IgA nephropathy, focal segmental glomerulosclerosis, membranous glomerulonephritis, minimal change disease, polycystic kidney disease and tubular interstitial nephritis. 
     
     
         32 - 37 . (canceled)